In vitro sensing methods for analyzing in vitro flowing fluids

ABSTRACT

Apparatus, systems and methods of analyzing an in vitro flowing fluid using an in vitro sensor that operates using non-optical frequencies such as in the radio or microwave frequency bands of the electromagnetic spectrum. The in vitro sensor directs one or more signals that are in the radio or microwave frequency bands of the electromagnetic spectrum into an in vitro flowing fluid and detects one or more responses that result from transmission of the signal(s) into the in vitro flowing fluid.

FIELD

This technical disclosure relates to apparatus, systems and methods ofanalyzing an in vitro flowing fluid via spectroscopic techniques usingnon-optical frequencies such as in the radio or microwave frequencybands of the electromagnetic spectrum.

BACKGROUND

A sensor that uses radio or microwave frequency bands of theelectromagnetic spectrum for in vivo medical diagnostics is disclosed inU.S. Pat. No. 10,548,503. Additional examples of sensors that use radioor microwave frequency bands of the electromagnetic spectrum fordetermining analytes in liquids are disclosed in U.S. Patent ApplicationPublication 2019/0008422 and U.S. Patent Application Publication2020/0187791.

SUMMARY

This disclosure relates generally to apparatus, systems and methods ofanalyzing an in vitro flowing fluid using an in vitro sensor thatoperates using non-optical frequencies such as in the radio or microwavefrequency bands of the electromagnetic spectrum. The in vitro sensordirects one or more signals that are in the radio or microwave frequencybands of the electromagnetic spectrum into an in vitro flowing fluid anddetects one or more responses that result from transmission of thesignal(s) into the in vitro flowing fluid. The term “in vitro” isintended to encompass a sensor and the fluid being outside the body of ahuman or animal during analysis regardless of whether the fluid beinganalyzed is a bodily fluid or a non-bodily fluid.

The analysis of the in vitro flowing fluid can include, but is notlimited to, one or more of the following: determining the presenceand/or amount of an analyte in the in vitro flowing fluid; determining asteady state condition of the in vitro flowing fluid as reflected in asteady state condition of the detected response(s); determining a changein condition of the in vitro flowing fluid as reflected in a change ofthe detected response(s). Other analyses are possible. A flowing fluidis a fluid that is in motion due to unbalanced forces acting on thefluid. The unbalanced forces may be due to gravity or mechanical meanssuch as a pump or a fan, or any others means for causing motion in afluid.

The word “fluid” as used in this description and in the claimsencompasses liquids, vapor, and gases and mixtures thereof. The fluidcan be a bodily fluid obtained from a human or animal body. Examples ofbodily fluids can include, but are not limited to, blood, urine, saliva,and semen. The fluid can be a non-bodily fluid that is not obtained froma human or animal body. A non-bodily fluid can be a fluid used in anindustrial and/or manufacturing process, or a fluid used in foodprocessing, or other types of non-bodily fluids used in other types ofindustries. Examples of non-bodily fluids are too exhaustive to list indetail but can include, but are not limited to, fuel, lubricating oil,mineral oil, edible oils, hydraulic fluid, water, alcoholic andnon-alcoholic beverages, food additives, acidic fluids, base fluids,paper pulp, industrial gases such as oxygen, nitrogen, and the like, andmany others. In general, the fluid can be human or non-human derived,animal or non-animal derived, biological or non-biological in nature, orany other fluid that one may wish to analyze using the in vitro sensorsdescribed herein.

In one embodiment described herein, an in vitro sensing system caninclude an in vitro sensor that is positioned adjacent to an in vitrofluid passageway that contains an in vitro flowing fluid. The in vitrosensor can include at least one transmit antenna and at least onereceive antenna, with the at least one transmit antenna positioned andarranged to transmit a signal into the in vitro flowing fluid in the invitro fluid passageway, wherein the signal is in a radio or microwavefrequency range of the electromagnetic spectrum. The at least onereceive antenna is positioned and arranged to detect a responseresulting from transmission of the signal by the at least one transmitantenna into the in vitro flowing fluid.

In another embodiment described herein, an in vitro sensing system canbe configured to sense an analyte in an in vitro flowing fluid. The invitro sensing system can include an in vitro sensor that is positionedadjacent to an in vitro fluid passageway that contains the in vitroflowing fluid with the analyte. The in vitro sensor can include at leastone transmit element and at least one receive element, where the atleast one transmit element is positioned and arranged to transmit asignal into the in vitro flowing fluid in the in vitro fluid passageway,and wherein the signal is in a radio or microwave frequency range of theelectromagnetic spectrum that is between about 10 kHz to about 100 GHz.In addition, the at least one receive element is positioned and arrangedto detect a response resulting from transmission of the signal by the atleast one transmit element into the in vitro flowing fluid.

In another embodiment described herein, an in vitro sensing method caninclude positioning an in vitro sensor adjacent to an in vitro fluidpassageway that contains an in vitro flowing fluid, wherein the in vitrosensor includes at least one transmit antenna and at least one receiveantenna. A signal that is in a radio or microwave frequency range of theelectromagnetic spectrum is transmitted from the at least one transmitantenna into the in vitro flowing fluid in the in vitro fluidpassageway. In addition, a response resulting from transmission of thesignal by the at least one transmit antenna into the in vitro flowingfluid is detected using the at least one receive antenna.

In another embodiment described herein, an in vitro sensing method forsensing an analyte in an in vitro flowing fluid is provided. The methodcan include positioning an in vitro sensor adjacent to an in vitro fluidpassageway that contains the in vitro flowing fluid with the analyte,wherein the in vitro sensor includes at least one transmit element andat least one receive element. A signal that is in a radio or microwavefrequency range of the electromagnetic spectrum that is between about 10kHz to about 100 GHz is transmitted from the at least one transmitelement into the in vitro flowing fluid in the in vitro fluidpassageway. In addition, a response that results from transmission ofthe signal by the at least one transmit element into the in vitroflowing fluid is detected using the at least one receive element.

DRAWINGS

FIG. 1A is a schematic depiction of a portion of in vitro sensing systemwith an in vitro sensor and an in vitro fluid passageway.

FIG. 1B is a schematic depiction similar to FIG. 1A but with the invitro sensor positioned within the in vitro fluid passageway.

FIG. 2 is a schematic depiction of an example of the in vitro sensorthat can be used.

FIG. 3 is a schematic depiction of the in vitro sensor according to anembodiment.

FIG. 4 depicts an example of an antenna array that can be used in the invitro sensor.

FIG. 5 illustrates an example of a response detected by the receiveantenna.

FIG. 6 illustrates another example of a response detected by the receiveantenna.

DETAILED DESCRIPTION

As used throughout this specification including the claims, the term “invitro” is intended to refer to a sensor and the fluid being outside thebody of a human or animal during analysis, regardless of whether thefluid being analyzed is a bodily fluid or a non-bodily fluid. The fluidbeing analyzed is a flowing fluid. A flowing fluid is a fluid that is inmotion due to unbalanced forces acting on the fluid. The unbalancedforces may be due to gravity or mechanical means such as a pump or afan, or any others means for causing motion in a fluid.

The word “fluid” as used in this description and in the claims refers toliquids, vapors, and gases and mixtures thereof. The fluid can be abodily fluid obtained from a human or animal body. Examples of bodilyfluids can include, but are not limited to, blood, urine, saliva, semen,feces, breast milk, vomit, body water, interstitial fluid, intracranialfluid, amniotic fluid, aqueous humor, bile, blood plasma, cerebrospinalfluid, chyle, chyme, endolymph, extracellular fluid, transcellularfluid, exudate, female ejaculate, gastric acid, hemolymph, lymph, mucus,pericardial fluid, perilymph, peritoneal fluid, phlegm, pus, rheum,synovial fluid, tears, transudate, vaginal lubrication, and vitreousbody. The fluid can be a non-bodily fluid that is not obtained from ahuman or animal body. A non-bodily fluid can be a fluid used in anindustrial and/or manufacturing process, or a fluid used in foodprocessing, or other types of non-bodily fluids used in other types ofindustries. Examples of non-bodily fluids are too exhaustive to list indetail but can include, but are not limited to, fuel, lubricating oil,mineral oil, edible oils, hydraulic fluid, water, alcoholic andnon-alcoholic beverages, food additives, acidic fluids, base fluids,paper pulp, industrial gases such as oxygen, nitrogen, and the like, andmany other fluids. In general, the fluid can be human or non-humanderived, animal or non-animal derived, biological or non-biological innature, or any other type of fluid that one may wish to analyze usingthe in vitro sensors described herein.

The flowing fluid herein can have a liquid as a primary component, i.e.the flowing fluid is at least 50% or at least 75% or at least 90% or atleast 95% liquid, with gas and/or solids included in the liquid. Inanother embodiment, the flowing fluid herein can have gas as a primarycomponent, i.e. the flowing fluid is at least 50% or at least 75% or atleast 90% or at least 95% gas, with liquid and/or solids included in thegas.

The flowing fluid herein can have a bodily fluid as a primary component,i.e. the flowing fluid is at least 50% or at least 75% or at least 90%or at least 95% bodily fluid, with other constituents included in thebodily fluid. In another embodiment, the flowing fluid can have anon-bodily fluid as a primary component, i.e. the flowing fluid is atleast 50% or at least 75% or at least 90% or at least 95% non-bodilyfluid, with other constituents included in the non-bodily fluid.

With reference to FIG. 1A, an example of an in vitro sensing system 10is illustrated. The system 10 includes at least one in vitro sensor 12and an in vitro fluid passageway 14 through which an in vitro fluidflows as indicated by the arrow A. The in vitro sensor 12 is positionedrelative to the in vitro fluid passageway 14 to permit the in vitrosensor 12 to sense the fluid flowing through the fluid passageway 14.For example, the in vitro sensor 12 can be positioned adjacent to thefluid passageway 14 and outside the fluid passageway 14. The sensor 12can be spaced from the fluid passageway 14 so that a gap exists betweenthe sensor 12 and the fluid passageway 14 as indicated in FIG. 1. Inanother embodiment, the sensor 12 may be in direct contact with thefluid passageway 14. If multiple sensors 12 are used, the sensors 12 canbe spaced from one another along the fluid passageway 14 and/or thesensors 12 can be located at the same general location of the fluidpassageway 14 but at circumferentially spaced locations around the fluidpassageway 14.

In another embodiment illustrated in FIG. 1B, the sensor 12 ispositioned adjacent to the fluid passageway 14 but within the fluidpassageway 14. The sensor 12 may be mounted on the interior surface ofthe wall of the passageway 14, or the sensor 12 may be supported in amanner so that the sensor 12 is spaced from the wall. The sensor 12 maybe fully immersed in the fluid flowing through the passageway 14, thesensor 12 may be completely outside of and not wetted by the fluidflowing through the passageway 14, or the sensor 12 may be partiallyimmersed in the fluid flowing through the passageway 14.

In general, the in vitro sensor 12 is configured to include at least onetransmit antenna/element 16 and at least one receive antenna/element 18.In FIG. 1A, the antennas 16, 18 may face the fluid passageway 14. The atleast one transmit antenna 16 is positioned and arranged to transmit asignal 20 into the fluid passageway 14 or into the fluid, wherein thesignal is in a radio or microwave frequency range of the electromagneticspectrum, for example between about 10 kHz to about 100 GHz. The atleast one receive antenna 18 is positioned and arranged to detect aresponse 22 resulting from transmission of the signal 20 by the at leastone transmit antenna 16 into the fluid. In some embodiments, thetransmit antenna and the receive antenna are decoupled from one anotherwhich improves the detection performance of the sensor 10.

With continued reference to FIG. 1A, the fluid passageway 14 includes asensing section 24 where the sensing of the in vitro flowing fluid bythe in vitro sensor 12 takes place. At least the sensing section 24, andpossibly the entire fluid passageway 14, is formed in a manner to permittravel of electromagnetic waves of the signal 20 and the response 22that are in the radio or microwave frequency bands of theelectromagnetic spectrum through at least one wall of the fluidpassageway 14 and into and from the flowing fluid in the fluidpassageway 14. In one embodiment, the sensing section 24 is locatedwhere the flowing fluid has laminar flow. In another embodiment, thesensing section 24 is located where the flowing fluid has turbulentflow.

The fluid passageway 14 can be a pipe, tube, conduit or the like thatpermits fluid to be analyzed to flow through the fluid passageway 14.The fluid passageway 14, as a whole or at the sensing section 24, can beformed from metal, plastic, glass, wood, ceramic, cardboard, paper, orother materials suitable for forming a fluid passageway 14. In oneembodiment, the sensing section 24 or the portion of the sensing section24 facing the sensor 12 is made from non-optically transparent material.In other words, the sensing section 24 that faces the sensor 12 need notbe transparent to light and can be made opaque to light.

The fluid passageway 14 can be part of a closed loop fluid system wherethe fluid passageway 14 forms part of a recirculation path for theflowing fluid. The fluid passageway 14 may also be part of a fluidsystem where the flowing fluid flows from one location to anotherlocation, with the sensing section 24 and the sensor 12 located at anydesired location along the fluid passageway 14. The fluid flow in fluidpassageway 14 may be caused by a mechanical device, such as a pump, fanor other fluid impelling device located upstream and/or downstream ofthe sensing section 24. In other embodiments, the fluid flow in fluidpassageway 14 may be caused by gravity.

In one embodiment, the sensor 12 can have a construction like thesensors disclosed in U.S. Pat. No. 10,548,503 which is incorporatedherein by reference in its entirety. In another embodiment, the sensor12 can have a construction like the sensors disclosed in U.S. PatentApplication Publication 2019/0008422. In another embodiment, the sensor12 can have a construction like the sensors disclosed in U.S. PatentApplication Publication 2020/0187791.

The sensor 12 may also have a construction like that disclosed inpending U.S. Patent Application 62/951,756 filed on Dec. 20, 2019 andentitled Non-Invasive Analyte Sensor And System With Decoupled TransmitAnd Receive Antennas, and in pending U.S. Patent Application 62/971,053filed on Feb. 6, 2020 and entitled Non-Invasive Detection Of An AnalyteUsing Different Combinations of Antennas That Can Transmit Or Receive,the entire contents of both applications are incorporated herein byreference.

In the sensor 12, the transmit antenna 16 transmits the signal 20, whichcan have at least two frequencies in the radio or microwave frequencyrange, toward and into the fluid passageway 14. The signal 20 with theat least two frequencies can be formed by separate signal portions, eachhaving a discrete frequency, that are transmitted separately at separatetimes at each frequency. In another embodiment, the signal 20 with theat least two frequencies may be part of a complex signal that includes aplurality of frequencies including the at least two frequencies. Thecomplex signal can be generated by blending or multiplexing multiplesignals together followed by transmitting the complex signal whereby theplurality of frequencies are transmitted at the same time. One possibletechnique for generating the complex signal includes, but is not limitedto, using an inverse Fourier transformation technique. The receiveantenna 18 detects the response 22 resulting from transmission of thesignal 20 by the transmit antenna 16 into the fluid passageway 14.

The transmit antenna 16 and the receive antenna 18 can be decoupled(which may also be referred to as detuned or the like) from one another.Decoupling refers to intentionally fabricating the configuration and/orarrangement of the transmit antenna 16 and the receive antenna 18 tominimize direct communication between the transmit antenna 16 and thereceive antenna 18, preferably absent shielding. Shielding between thetransmit antenna 16 and the receive antenna 18 can be utilized. However,the transmit antenna 16 and the receive antenna 18 are decoupled evenwithout the presence of shielding.

Referring to FIG. 2, an embodiment of the sensor 12 is illustrated. InFIG. 2, elements that are the same as elements in FIG. 1 are referencedusing the same reference numerals. The sensor 12 is depicted relative tothe fluid passageway 14 containing the flowing fluid indicated by thearrow A. In this example, the fluid is indicated as including an analyte30 which for sake of explanation are depicted with enlarged circles. Inthis example, the sensor 12 is depicted as including an antenna arraythat includes the transmit antenna/element 16 (hereinafter “transmitantenna 16”) and the receive antenna/element 18 (hereinafter “receiveantenna 18”). The sensor 12 further includes a transmit circuit 32, areceive circuit 34, and a controller 36. As discussed further below, thesensor 12 can also include a power supply, such as a battery (not shownin FIG. 2).

The transmit antenna 16 is positioned, arranged and configured totransmit the signal 20 that is the radio frequency (RF) or microwaverange of the electromagnetic spectrum into the fluid passageway 14. Thetransmit antenna 16 can be an electrode or any other suitabletransmitter of electromagnetic signals in the radio frequency (RF) ormicrowave range. The transmit antenna 16 can have any arrangement andorientation relative to the fluid passageway 14 that is sufficient toallow the sensing described herein to take place. In one non-limitingembodiment, the transmit antenna 16 can be arranged to face in adirection that is substantially toward the fluid passageway 14.

The signal 20 transmitted by the transmit antenna 16 is generated by thetransmit circuit 32 which is electrically connectable to the transmitantenna 16. The transmit circuit 32 can have any configuration that issuitable to generate a transmit signal to be transmitted by the transmitantenna 16. Transmit circuits for generating transmit signals in the RFor microwave frequency range are well known in the art. In oneembodiment, the transmit circuit 32 can include, for example, aconnection to a power source, a frequency generator, and optionallyfilters, amplifiers or any other suitable elements for a circuitgenerating an RF or microwave frequency electromagnetic signal. In anembodiment, the signal generated by the transmit circuit 32 can have atleast two discrete frequencies (i.e. a plurality of discretefrequencies), each of which is in the range from about 10 kHz to about100 GHz. In another embodiment, each of the at least two discretefrequencies can be in a range from about 300 MHz to about 6000 MHz. Inan embodiment, the transmit circuit 32 can be configured to sweepthrough a range of frequencies that are within the range of about 10 kHzto about 100 GHz, or in another embodiment a range of about 300 MHz toabout 6000 MHz. In an embodiment, the transmit circuit 32 can beconfigured to produce a complex transmit signal, the complex signalincluding a plurality of signal components, each of the signalcomponents having a different frequency. The complex signal can begenerated by blending or multiplexing multiple signals together followedby transmitting the complex signal whereby the plurality of frequenciesare transmitted at the same time.

The receive antenna 18 is positioned, arranged, and configured to detectthe one or more electromagnetic response signals 22 that result from thetransmission of the transmit signal 20 by the transmit antenna 16 intothe fluid passageway 14. The receive antenna 18 can be an electrode orany other suitable receiver of electromagnetic signals in the radiofrequency (RF) or microwave range. In an embodiment, the receive antenna18 is configured to detect electromagnetic signals having at least twofrequencies, each of which is in the range from about 10 kHz to about100 GHz, or in another embodiment a range from about 300 MHz to about6000 MHz. The receive antenna 18 can have any arrangement andorientation relative to the fluid passageway 14 that is sufficient toallow detection of the response signal(s) 22 to allow the sensingdescribed herein to take place. In one non-limiting embodiment, thereceive antenna 18 can be arranged to face in a direction that issubstantially toward the fluid passageway 14.

The receive circuit 34 is electrically connectable to the receiveantenna 18 and conveys the received response from the receive antenna 18to the controller 36. The receive circuit 34 can have any configurationthat is suitable for interfacing with the receive antenna 18 to convertthe electromagnetic energy detected by the receive antenna 18 into oneor more signals reflective of the response signal(s) 22. Theconstruction of receive circuits are well known in the art. The receivecircuit 34 can be configured to condition the signal(s) prior toproviding the signal(s) to the controller 36, for example throughamplifying the signal(s), filtering the signal(s), or the like.Accordingly, the receive circuit 34 may include filters, amplifiers, orany other suitable components for conditioning the signal(s) provided tothe controller 36. In an embodiment, at least one of the receive circuit34 or the controller 36 can be configured to decompose or demultiplex acomplex signal, detected by the receive antenna 18, including aplurality of signal components each at different frequencies into eachof the constituent signal components. In an embodiment, decomposing thecomplex signal can include applying a Fourier transform to the detectedcomplex signal. However, decomposing or demultiplexing a receivedcomplex signal is optional. Instead, in an embodiment, the complexsignal detected by the receive antenna can be analyzed as a whole (i.e.without demultiplexing the complex signal) to detect the analyte as longas the detected signal provides enough information to make the analytedetection.

The controller 36 controls the operation of the sensor 12. Thecontroller 36, for example, can direct the transmit circuit 32 togenerate a transmit signal to be transmitted by the transmit antenna 16.The controller 36 further receives signals from the receive circuit 34.The controller 36 can optionally process the signals from the receivecircuit 34 to perform the detection described herein. In one embodiment,the controller 36 may optionally be in communication with at least oneexternal device 38 such as a user device and/or a remote server 40, forexample through one or more wireless connections such as Bluetooth,wireless data connections such a 4G, 5G, LTE or the like, or Wi-Fi. Ifprovided, the external device 38 and/or remote server 40 may process (orfurther process) the signals that the controller 36 receives from thereceive circuit 34. If provided, the external device 38 may be used toprovide communication between the sensor 12 and the remote server 40,for example using a wired data connection or via a wireless dataconnection or Wi-Fi of the external device 38 to provide the connectionto the remote server 40.

With continued reference to FIG. 2, the sensor 12 may include a sensorhousing 42 (shown in dashed lines) that defines an interior space 44.Components of the sensor 12 may be attached to and/or disposed withinthe housing 42. For example, the transmit antenna 16 and the receiveantenna 18 are attached to the housing 42. In some embodiments, theantennas 16, 18 may be entirely or partially within the interior space44 of the housing 42. In some embodiments, the antennas 16, 18 may beattached to the housing 42 but at least partially or fully locatedoutside the interior space 44. In some embodiments, the transmit circuit32, the receive circuit 34 and the controller 36 are attached to thehousing 42 and disposed entirely within the sensor housing 42.

The receive antenna 18 may be decoupled or detuned with respect to thetransmit antenna 16 such that electromagnetic coupling between thetransmit antenna 16 and the receive antenna 18 is reduced. Thedecoupling of the transmit antenna 16 and the receive antenna 18increases the portion of the signal(s) detected by the receive antenna16 that is the response signal(s) 22 from the fluid passageway 14, andminimizes direct receipt of the transmitted signal 20 by the receiveantenna 18. The decoupling of the transmit antenna 16 and the receiveantenna 18 results in transmission from the transmit antenna 16 to thereceive antenna 18 having a reduced forward gain (S₂₁) and an increasedreflection at output (S₂₂) compared to antenna systems having coupledtransmit and receive antennas.

In an embodiment, coupling between the transmit antenna 16 and thereceive antenna 18 is 95% or less. In another embodiment, couplingbetween the transmit antenna 16 and the receive antenna 18 is 90% orless. In another embodiment, coupling between the transmit antenna 16and the receive antenna 18 is 85% or less. In another embodiment,coupling between the transmit antenna 16 and the receive antenna 18 is75% or less.

Any technique for reducing coupling between the transmit antenna 16 andthe receive antenna 18 can be used. For example, the decoupling betweenthe transmit antenna 16 and the receive antenna 18 can be achieved byone or more intentionally fabricated configurations and/or arrangementsbetween the transmit antenna 16 and the receive antenna 18 that issufficient to decouple the transmit antenna 16 and the receive antenna18 from one another.

For example, in one embodiment, the decoupling of the transmit antenna16 and the receive antenna 18 can be achieved by intentionallyconfiguring the transmit antenna 16 and the receive antenna 18 to havedifferent geometries from one another. Intentionally differentgeometries refers to different geometric configurations of the transmitand receive antennas 16, 18 that are intentional. Intentionaldifferences in geometry are distinct from differences in geometry oftransmit and receive antennas that may occur by accident orunintentionally, for example due to manufacturing errors or tolerances.

Another technique to achieve decoupling of the transmit antenna 16 andthe receive antenna 18 is to provide appropriate spacing between eachantenna 16, 18 that is sufficient to decouple the antennas 16, 18 andforce a proportion of the electromagnetic lines of force of thetransmitted signal 20 into the fluid passageway 14 thereby minimizing oreliminating as much as possible direct receipt of electromagnetic energyby the receive antenna 18 directly from the transmit antenna 16 withouttraveling into the fluid passageway. The appropriate spacing betweeneach antenna 16, 18 can be determined based upon factors that include,but are not limited to, the output power of the signal from the transmitantenna 16, the size of the antennas 16, 18, the frequency orfrequencies of the transmitted signal, and the presence of any shieldingbetween the antennas. This technique helps to ensure that the responsedetected by the receive antenna 18 is performing the desired sensing andis not just the transmitted signal 20 flowing directly from the transmitantenna 16 to the receive antenna 18. In some embodiments, theappropriate spacing between the antennas 16, 18 can be used togetherwith the intentional difference in geometries of the antennas 16, 18 toachieve decoupling.

In one embodiment, the transmit signal that is transmitted by thetransmit antenna 16 can have at least two different frequencies, forexample upwards of 7 to 12 different and discrete frequencies. Inanother embodiment, the transmit signal can be a series of discrete,separate signals with each separate signal having a single frequency ormultiple different frequencies.

In one embodiment, the transmit signal (or each of the transmit signals)can be transmitted over a transmit time that is less than, equal to, orgreater than about 300 ms. In another embodiment, the transmit time canbe than, equal to, or greater than about 200 ms. In still anotherembodiment, the transmit time can be less than, equal to, or greaterthan about 30 ms. The transmit time could also have a magnitude that ismeasured in seconds, for example 1 second, 5 seconds, 10 seconds, ormore. In an embodiment, the same transmit signal can be transmittedmultiple times, and then the transmit time can be averaged. In anotherembodiment, the transmit signal (or each of the transmit signals) can betransmitted with a duty cycle that is less than or equal to about 50%.

Referring to FIG. 3, an example configuration of the sensor 12 isillustrated. In FIG. 3, elements that are identical or similar toelements in FIGS. 1 and 2 are referenced using the same referencenumerals. In FIG. 3, the antennas 16, 18 are disposed on one surface ofa substrate 50 which can be, for example, a printed circuit board. FIG.4 illustrates an example of the antennas 16, 18 in the form of metaltraces disposed on the substrate 50. Returning to FIG. 3, at least onebattery 52, such as a rechargeable battery, is provided above thesubstrate 50, for providing power to the sensor 12. In addition, adigital printed circuit board 54 is provided on which the transmitcircuit, the receive circuit, and the controller and other electronicsof the sensor 12 can be disposed. The substrate 50 and the digitalprinted circuit board 54 are electrically connected via any suitableelectrical connection, such as a flexible connector 56. An RF shield 58may optionally be positioned between the antennas 16, 18 and the battery52, or between the antennas 16, 18 and the digital printed circuit board54, to shield the circuitry and electrical components from RFinterference.

As depicted in FIG. 3, all of the elements of the sensor 12, includingthe antennas 16, 18, the transmit circuit, the receive circuit, thecontroller, the battery 52 and the like are contained entirely withinthe interior space 44 of the housing 42. In an alternative embodiment, aportion of or the entirety of each antenna 16, 18 can project below abottom wall 60 of the housing 42. In another embodiment, the bottom ofeach antenna 16, 18 can be level with the bottom wall 60, or they can beslightly recessed from the bottom wall 60.

The housing 42 of the sensor 10 can have any configuration and size thatone finds suitable for employing in the sensor 10 described herein. Inone embodiment, the housing 42 can have a maximum length dimension L_(H)no greater than 50 mm, a maximum width dimension W_(H) no greater than50 mm, and a maximum thickness dimension T_(H) no greater than 25 mm,for a total interior volume of no greater than about 62.5 cm³. However,other dimensions are possible.

In addition, with continued reference to FIG. 3, there can be a maximumspacing D_(max) and a minimum spacing D_(min) between the transmitantenna 16 and the receive antenna 18. The maximum spacing D_(max) maybe dictated by the maximum size of the housing 42. In one embodiment,the maximum spacing D_(max) can be about 50 mm. In one embodiment, theminimum spacing D_(min) can be from about 1.0 mm to about 5.0 mm.

The analysis of the in vitro flowing fluid, by the sensor 12 or by anexternal device using data obtained by the sensor 12, can include, butis not limited to, one or more of the following: determining thepresence and/or amount of an analyte, such as the analyte 30 in FIG. 3,in the in vitro flowing fluid; determining a steady state condition ofthe in vitro flowing fluid as reflected in a steady state condition ofthe detected response(s); determining a change in condition of the invitro flowing fluid as reflected in a change of the detectedresponse(s). Other analyses are possible.

For example, in some embodiments, the response or signal(s) 22 detectedby the receive antenna 18 can be analyzed to detect the analyte 30 inthe flowing fluid based on the intensity of the received signal(s) andreductions in intensity at one or more frequencies where the analyteabsorbs the transmitted signal. The signal(s) detected by the receiveantenna can be complex signals including a plurality of signalcomponents, each signal component being at a different frequency. In anembodiment, the detected complex signals can be decomposed into thesignal components at each of the different frequencies, for examplethrough a Fourier transformation. In an embodiment, the complex signaldetected by the receive antenna can be analyzed as a whole (i.e. withoutdemultiplexing the complex signal) to detect the analyte as long as thedetected signal provides enough information to make the analytedetection. In addition, the signal(s) detected by the receive antennacan be separate signal portions, each having a discrete frequency.

In one embodiment, the sensor 12 can be used to detect the presence ofat least one analyte in the flowing fluid. In another embodiment, thesensor can detect an amount or a concentration of the at least oneanalyte in the flowing fluid. The analyte(s) can be any analyte that onemay wish to detect. The analyte can be human or non-human, animal ornon-animal, biological or non-biological. For example, the analyte(s)can include, but is not limited to, one or more of blood glucose, bloodcholesterol, blood alcohol, white blood cells, or luteinizing hormone.The analyte(s) can include, but is not limited to, a chemical, acombination of chemicals, a virus, bacteria, or the like. The analytecan be a chemical included in another medium, with non-limiting examplesof such media including a fluid containing the at least one analyte, forexample blood, interstitial fluid, cerebral spinal fluid, lymph fluid orurine. The analyte(s) may also be a non-human, non-biological particlesuch as a mineral or a contaminant.

The analyte(s) that can be detected can include, for example, naturallyoccurring substances, artificial substances, metabolites, and/orreaction products. As non-limiting examples, the at least one analytecan include, but is not limited to, insulin, acarboxyprothrombin;acylcarnitine; adenine phosphoribosyl transferase; adenosine deaminase;albumin; alpha-fetoprotein; amino acid profiles (arginine (Krebs cycle),histidine/urocanic acid, homocysteine, phenylalanine/tyrosine,tryptophan); andrenostenedione; antipyrine; arabinitol enantiomers;arginase; benzoylecgonine (cocaine); biotinidase; biopterin; c-reactiveprotein; carnitine; pro-BNP; BNP; troponin; carnosinase; CD4;ceruloplasmin; chenodeoxycholic acid; chloroquine; cholesterol;cholinesterase; conjugated 1-β hydroxy-cholic acid; cortisol; creatinekinase; creatine kinase MM isoenzyme; cyclosporin A; d-penicillamine;de-ethylchloroquine; dehydroepiandrosterone sulfate; DNA (for example,DNA associated with acetylator polymorphism, alcohol dehydrogenase,alpha 1-antitrypsin, cystic fibrosis, Duchenne/Becker musculardystrophy, analyte-6-phosphate dehydrogenase, hemoglobin A, hemoglobinS, hemoglobin C, hemoglobin D, hemoglobin E, hemoglobin F, D-Punjab,beta-thalassemia, hepatitis B virus, HCMV, HIV-1, HTLV-1, Leberhereditary optic neuropathy, MCAD, RNA, PKU, Plasmodium vivax, sexualdifferentiation, or 21-deoxycortisol); desbutylhalofantrine;dihydropteridine reductase; diptheria/tetanus antitoxin; erythrocytearginase; erythrocyte protoporphyrin; esterase D; fattyacids/acylglycines; free β-human chorionic gonadotropin; freeerythrocyte porphyrin; free thyroxine (FT4); free tri-iodothyronine(FT3); fumarylacetoacetase; galactose/gal-1-phosphate;galactose-1-phosphate uridyltransferase; gentamicin; analyte-6-phosphatedehydrogenase; glutathione; glutathione perioxidase; glycocholic acid;glycosylated hemoglobin; halofantrine; hemoglobin variants;hexosaminidase A; human erythrocyte carbonic anhydrase I;17-alpha-hydroxyprogesterone; hypoxanthine phosphoribosyl transferase;immunoreactive trypsin; lactate; lead; lipoproteins ((a), B/A-1, β);lysozyme; mefloquine; netilmicin; phenobarbitone; phenytoin;phytanic/pristanic acid; progesterone; prolactin; prolidase; purinenucleoside phosphorylase; quinine; reverse tri-iodothyronine (rT3);selenium; serum pancreatic lipase; sissomicin; somatomedin C; specificantibodies (such as antibodies for or associated with an adenovirus,anti-nuclear antibodies, anti-zeta antibodies, arbovirus, Aujeszky'sdisease virus, dengue virus, Dracunculus medinensis, Echinococcusgranulosus, Entamoeba histolytica, enterovirus, Giardia duodenalisa,Helicobacter pylori, hepatitis B virus, herpes virus, HIV-1, IgE (atopicdisease), influenza virus, Leishmania donovani, leptospira,measles/mumps/rubella, Mycobacterium leprae, Mycoplasma pneumoniae,Myoglobin, Onchocerca volvulus, parainfluenza virus, Plasmodiumfalciparum, polio virus, Pseudomonas aeruginosa, respiratory syncytialvirus, rickettsia (scrub typhus), Schistosoma mansoni, Toxoplasmagondii, Trepenoma pallidium, Trypanosoma cruzi/rangeli, vesicularstomatis virus, Wuchereria bancrofti, yellow fever virus); specificantigens (hepatitis B virus, HIV-1); succinylacetone; sulfadoxine;theophylline; thyrotropin (TSH); thyroxine (T4); thyroxine-bindingglobulin; trace elements; transferrin; UDP-galactose-4-epimerase; urea;uroporphyrinogen I synthase; vitamin A; white blood cells; and zincprotoporphyrin.

The analyte(s) can also include one or more chemicals introduced intothe flowing fluid. The analyte(s) can include a marker such as acontrast agent, a radioisotope, or other chemical agent. The analyte(s)can include a fluorocarbon-based synthetic blood. The analyte(s) caninclude a drug or pharmaceutical composition, with non-limiting examplesincluding ethanol; cannabis (marijuana, tetrahydrocannabinol, hashish);inhalants (nitrous oxide, amyl nitrite, butyl nitrite,chlorohydrocarbons, hydrocarbons); cocaine (crack cocaine); stimulants(amphetamines, methamphetamines, Ritalin, Cylert, Preludin, Didrex,PreState, Voranil, Sandrex, Plegine); depressants (barbiturates,methaqualone, tranquilizers such as Valium, Librium, Miltown, Serax,Equanil, Tranxene); hallucinogens (phencyclidine, lysergic acid,mescaline, peyote, psilocybin); narcotics (heroin, codeine, morphine,opium, meperidine, Percocet, Percodan, Tussionex, Fentanyl, Darvon,Talwin, Lomotil); designer drugs (analogs of fentanyl, meperidine,amphetamines, methamphetamines, and phencyclidine, for example,Ecstasy); anabolic steroids; and nicotine. The analyte(s) can includeother drugs or pharmaceutical compositions. The analyte(s) can includeneurochemicals or other chemicals generated within the body, such as,for example, ascorbic acid, uric acid, dopamine, noradrenaline,3-methoxytyramine (3MT), 3,4-Dihydroxyphenylacetic acid (DOPAC),Homovanillic acid (HVA), 5-Hydroxytryptamine (5HT), and5-Hydroxyindoleacetic acid (FHIAA).

FIG. 5 depicts an example of an analysis that involves determining asteady state condition of the in vitro flowing fluid as reflected in asteady state condition of the detected response(s). FIG. 5 depicts anexample of the response signal 22 plotted versus time. In this example,the response signal 22 is shown as changing up to time t₁ and thenremaining substantially steady after time t₁. The analysis using thesensor 12 can include looking for the response signal 22 to reach asteady state which can indicate a desired condition of the flowing fluidin the fluid passageway. A desired condition can include, but is notlimited to, an analyte reaching a steady state level in a fluid thatcarries the analyte.

FIG. 6 depicts an example of an analysis that involves determining achange in condition of the in vitro flowing fluid as reflected in achange of the detected response signal 22. FIG. 6 depicts an example ofthe response signal 22 plotted versus time. In this example, theresponse signal 22 is shown as remaining steady up to time t₁ at whichtime the signal changes significantly in some manner (FIG. 6 depicts thesignal 22 increasing or decreasing at time t₁). The analysis using thesensor 12 can include looking for a change in the response signal 22which can indicate a significant and perhaps undesired change in theflowing fluid in the fluid passageway. A change in the flowing fluid caninclude, but is not limited to, a significant change occurring in thepresence or amount of an analyte in a fluid that carries the analyte.

The examples disclosed in this application are to be considered in allrespects as illustrative and not limitative. The scope of the inventionis indicated by the appended claims rather than by the foregoingdescription; and all changes which come within the meaning and range ofequivalency of the claims are intended to be embraced therein.

1. An in vitro sensing method, comprising: positioning an in vitrosensor adjacent to an in vitro fluid passageway that contains an invitro flowing fluid, wherein the in vitro sensor includes at least onetransmit antenna and at least one receive antenna; transmitting a signalthat is in a radio or microwave frequency range of the electromagneticspectrum from the at least one transmit antenna into the in vitroflowing fluid in the in vitro fluid passageway; and detecting a responseusing the at least one receive antenna resulting from transmission ofthe signal by the at least one transmit antenna into the in vitroflowing fluid.
 2. The in vitro sensing method of claim 1, wherein the atleast one transmit antenna and the at least one receive antenna aredecoupled from one another; and the in vitro sensor further includes: atransmit circuit that is electrically connectable to the at least onetransmit antenna, the transmit circuit is configured to generate thesignal to be transmitted by the at least one transmit antenna; and areceive circuit that is electrically connectable to the at least onereceive antenna, the receive circuit is configured to receive a responsedetected by the at least one receive antenna.
 3. The in vitro sensingmethod of claim 1, comprising transmitting the signal in a frequencyrange that is between about 10 kHz to about 100 GHz.
 4. The in vitrosensing method of claim 1, wherein the in vitro flowing fluid comprisesa liquid as a primary component.
 5. The in vitro sensing method of claim1, wherein the in vitro flowing fluid comprises a gas as a primarycomponent.
 6. The in vitro sensing method of claim 1, wherein the invitro flowing fluid comprises a bodily fluid as a primary component. 7.The in vitro sensing method of claim 1, wherein the in vitro flowingfluid comprises a non-bodily fluid as a primary component.
 8. The invitro sensing method of claim 1, comprising transmitting the signal fromthe transmit antenna into the in vitro flowing fluid where the in vitroflowing fluid has laminar flow.
 9. The in vitro sensing method of claim1, comprising positioning the in vitro sensor outside the in vitro fluidpassageway, and comprising positioning the in vitro sensor so that theat least one transmit antenna and the at least one receive antenna facea portion of the in vitro fluid passageway that is formed from anon-optically transparent material.
 10. The in vitro sensing method ofclaim 1, comprising positioning the in vitro sensor inside the in vitrofluid passageway.
 11. An in vitro sensing method for sensing an analytein an in vitro flowing fluid, comprising: positioning an in vitro sensoradjacent to an in vitro fluid passageway that contains the in vitroflowing fluid with the analyte, wherein the in vitro sensor includes atleast one transmit element and at least one receive element;transmitting a signal that is in a radio or microwave frequency range ofthe electromagnetic spectrum that is between about 10 kHz to about 100GHz from the at least one transmit element into the in vitro flowingfluid; and detecting a response using the at least one receive elementresulting from transmission of the signal by the at least one transmitelement into the in vitro flowing fluid.
 12. The in vitro sensing methodof claim 11, wherein the at least one transmit element and the at leastone receive element are decoupled from one another; and the in vitrosensor further includes: a transmit circuit that is electricallyconnectable to the at least one transmit element, the transmit circuitis configured to generate the signal to be transmitted by the at leastone transmit element; and a receive circuit that is electricallyconnectable to the at least one receive element, the receive circuit isconfigured to receive a response detected by the at least one receiveelement.
 13. The in vitro sensing method of claim 11, wherein the invitro flowing fluid comprises a liquid as a primary component.
 14. Thein vitro sensing method of claim 11, wherein the in vitro flowing fluidcomprises a gas as a primary component.
 15. The in vitro sensing methodof claim 11, wherein the in vitro flowing fluid comprises a bodily fluidas a primary component.
 16. The in vitro sensing method of claim 11,wherein the in vitro flowing fluid comprises a non-bodily fluid as aprimary component.
 17. The in vitro sensing method of claim 11,comprising transmitting the signal from the transmit antenna into the invitro flowing fluid where the in vitro flowing fluid has laminar flow.18. The in vitro sensing method of claim 11, comprising positioning thein vitro sensor outside the in vitro fluid passageway, and comprisingpositioning the in vitro sensor so that the at least one transmitantenna and the at least one receive antenna face a portion of the invitro fluid passageway that is formed from a non-optically transparentmaterial.
 19. The in vitro sensing method of claim 11, comprisingpositioning the in vitro sensor inside the in vitro fluid passageway.20. The in vitro sensing method of claim 11, wherein the analyte in thein vitro flowing fluid comprises cholesterol, blood glucose, bloodalcohol, white blood cells, or luteinizing hormone.